Genetics of Cardiovascular Diseases

Name: Genetics of Cardiovascular Diseases
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Description: Genetics of Cardiovascular Diseases

Genetics of Cardiovascular Diseases
Jacques Genest MD Cardiovascular Genetics Laboratory McGill University Health Center

Genetics loads the gun, environment pulls the trigger
Elliott Joslin Age is a major cardiovascular risk factor Framingham Heart Study The older I get, the better I was A Cowboy

Human Biochemical Genetics 2009 Genetics of Cardiovascular Diseases
General Principles Historical Aspects Monogenic Disorders Genome-wide Association (GWA)Studies Mendelian Randomization Epigenetics

Genetics of CAD Monogenic Disorders Rare, extremes traits
Candidate genes association studies Genome-wide scan associations Rare, extremes traits Biased, often not replicated Unbiased, weak clinical relevance

Genetics of CAD Watkins et al. Nature Reviews Genetics
published online 07 February 2006

Genetics and CAD Genetics of CAD is complex.
Family Hx of premature CAD increases risk > 2.0 fold <55 for father; <65 for mother Corrected for other RF Association weaker in INTERHEART (case ascertainment of familial CAD weaker than in FHS). Lloyd-Jones D et al. Lancet 2004;291:2204

Genetics and Survival Genes Environment 50 100 Age

General Principles

Chromosomes and DNA

Types of Genetic Disease
Single Gene (Mendelian) Disorders- e.g. sickle cell disease, familial hypercholesterolemia, cystic fibrosis Multifactorial or Complex Diseases- e.g. diabetes, asthma, heart disease -Family/Twin/Adoption Studies Chromosomal Disorders- e.g. trisomy 21 (Down syndrome), XO Turner syndrome

Copy Number of Variant Repeats
Nature 23 Nov 2006

Genetics of Complex Traits
13

Historical Aspects

Cholesterol Synthesis Pathway
Istvan E and Deisenhofer J. Science 2001;292:

Risk Factors for CAD Cigarette Hypertension LDL-cholesterol (apo B)
HDL-cholesterol Diabetes Age Atherosclerosis Circulation 2000;101:

INTERHEART: Conclusions
Risk Factor OR Population Attributable Risk Smoking 2.87 35.7% Apo B/AI 3.25 49.2% Hypertension 1.91 17.9% Diabetes 2.37 9.9% Abd. Obesity 1.62 20.1% Fruits / Vegetables 0.70 13.7% Alcohol 0.91 6.7% Physical Activity 0.86 12.2%

Monogenic Disorders

19

Case 1 Familial Hypercholesterolemia Heterozygous
Frequency 1:500 (up to 1:80 in Lac St-Jean) Tendinous xanthomas LDL-Receptor gene defect LDL-C 2x ULN

Case 2b Familial Hypercholesterolemia Homozygous Very rare (1:106)
Premature CAD in childhood Extracorporeal LDL removal

Familial Hypercholesterolemia
Most frequent genetic disorder associated with premature CAD (3-5%) of patients. LDL-receptor defects underlie the majority of cases CAD develops in men years, in women years. Respond to statins (+ bile acid binding resins) (+ intestinal cholesterol absorption inhibitors ezetimibe)

Within intestinal cells (and other body cells) some of the absorbed cholesterol is esterified to fatty acids, forming cholesteryl esters. (R = fatty acid chain) The enzyme that catalyzes cholesterol esterification in plasma is LCAT (Lecithin:Cholesterol Acyl Transferase) and intra-cellularly, ACAT (Acyl CoA: Cholesterol Acyl Transferase).

H O Cholesterol O Cholesteryl Ester LCAT

Triglycerides Lipoprotein Lipase

Phospholipids Choline Phosphate Glycerol Acyl Chains (Fatty acids) CH3
O=P-O CH2-CH-CH2 O=C C=O R2 CH3-N-CH3 CH3 R1 Choline Phosphate Glycerol Acyl Chains (Fatty acids)

Apolipoprotein Phospholipid Triglyceride Cholesterol Cholesteryl ester

Density (g/ml) Diameter (nm) 0.95- 1.006- 1.02- 1.06- 1.10- 1.20- 5 10
VLDL 1.006- IDL CHYLOMICRON RENNANTS 1.02- Density (g/ml) LDL 1.06- HDL2 1.10- HDL3 1.20- 5 10 20 40 60 80 1000 Diameter (nm)

Lipoprotein Metabolism LDL-R
FFA Liver HL LPL Exogenous Pathway Chylo Remnant Chylomicron Peripheral Cells Free Cholesterol ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Intestine X HL Steroidogenic Cells LCAT Nascent HDL HDL3 HDL2 LDL Liver X ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol CETP PLTP Tg Endogenous Pathway CE Liver 3 VLDL LPL HL IDL FFA

LDL Receptor Cells take up LDL by receptor-mediated endocytosis.
The cholesterol in LDL is then used by cells, e.g., for synthesis of cellular membranes. The LDL receptor was identified by M. Brown & J. Goldstein, who were awarded the Nobel prize for this achievement.

Cholesterol Hepatic Cell VLDL-R LRP LDL-R IDL VLDL ApoB ApoE ApoB ApoE
Endosome VLDL-R LRP ApoB LDL-R LDL Cholesterol HMG CoA Red ACAT Cholesteryl esters Fatty acids sER Lipoprotein assembly and secretion Bile acids VLDL Hepatic Cell

LDL-R Pathway Animation

Familial Hypercholesterolemia
LDL-R gene (19p13) (Familial Hypercholesterolemia) LDL-Receptor Defects Apo B gene (2q23) (Familial Defective apo B) Apolipoprotein B Mutations PCSK9 (proprotein convertase subtilisin/kexin type 9) (1p32) Autosomal Dominant Hypercholesterolemia ARH gene (1p ) (Autosomal Recessive Hypercholesterolemia) LDL-R internalization defect LDL Overproduction Defects (1q21)(Familial Combined Hyperlipidemia)

Molecular Causes of Familial Hypercholesterolemia (FH)
ApoB: Familial defective Apo B LDL-R: Primary familial hypercholesterolemia ARH: Autosomal recessive familial Hypercholesterolemia PCSK9: Proprotein convertase subtilisin/kexin type 9

LDL Apheresis + Atorvastatin Mean LDL-C (mmol/L) Mean LDL-C (mg/dL)
500 Apheresis 400 300 Mean LDL-C (mmol/L) Mean LDL-C (mg/dL) 200 + Atorvastatin 100 1992 1993 1994 1995 1996 1997 1998 1999 Time (years) Genest J. NEJM 1999;341:490

PCSK9 Life-long exposure to risk factor:
Principles of Mendelian Randomization

PCSK9 Gene Mutation (African-Americans)
Cohen J. et al. NEJM 2006;354:1264

Mendelian randomization
Mendelian randomization. The effect of life-long genetic variability of risk factor (exposure) on the disease process.

High-Density Lipoproteins
HDL High-Density Lipoproteins

Case: Tangier Disease Tangier Disease (Familial HDL Deficiency)
Very rare Orange tonsils Hepatosplenomegaly Neuropathy Premature CAD Lymphoid tissue foam cells (incl. intestinal mucosa)

Lipoprotein Metabolism: HDL
FFA Liver HL LPL Exogenous Pathway Chylo Remnant Chylomicron 1 Peripheral Cells Free Cholesterol X ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Intestine HL Steroidogenic Cells LCAT Nascent HDL HDL3 HDL2 LDL Liver ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol CETP PLTP Tg Endogenous Pathway CE 4 Liver 3 VLDL LPL HL IDL FFA

Cholesterol ApoB LDL Nascent HDL Lipid-free apo AI ABCA1 LDL-R LCAT
Endosome ApoB LDL-R LDL LCAT Cholesterol HMG CoA Red ACAT sER Cholesteryl ester Stores HDL3

ABCA1 Full-transporter Phospholipid and (cholesterol) efflux to apoA-I
Early HDL maturation LxR/RxR - COOH NH2- cholesterol & phospholipid ATP ADP+Pi ATP ADP+Pi

HDL Biogenesis HDL-C Mass ABCA1 Liver 80% ABCA1 ApoAI ABCG1
Macrophage <5% ApoE ABCA1 ApoAI Intestine 20%

ABCA1 is Essential for HDL Biogenesis
LxR/RxR

ABC Transporters and Human Disease
HUGO Gene Disease Function ABCA1 ABC1 Tangier / FHD PL, Chol transport ABCA3 Sufractant Deficiency PL transport ABCA4 ABCR Stargardt Disease Rod receptors ABCB4 MDR3 Familial Intrahepatic Cholestasis 3 Biliary PL secretion ABCB7 ABC7 X-linked sideroblastic anemia Iron transport ABC11 BSEP Familial intrahepatic cholestasis 2 Bile acid transport ABCC2 MRP2 Dubin-Johnson Syndrome Biliary secretion ABCC6 Pseudoxanthoma elasticum ABCC7 CFTR Cystic Fibrosis Electrolyte transport ABCC8 SUR1 Persistent hyperinsulinemic hypoglycemia Insulin secretion ABCD1 ALD X-linked adrenoleukodystrophy Fatty acid ABCD3 PMP70 Zellweger syndrome Peroxysome formation ABCG5,8 Sitosterolemia Sitosterol transport ABCB3 TAP2 HSV infection

ABCA1 Mutations

HDL-C is Highly Heritable
Studies in twins (n=9) Family studies (n=14) Heritability of HDL-C 0.24 – 0.83 Canadian data: 0.58 Peackock JM ATVB 2001;21:1823

Candidate Gene Sequence Variants in Low HDL subjects
Cohen JC et al. Science 2004;305:869 ABCA1 variants seen in ~10% of low HDL-C (p<0.001) Frikke-Schmidt R et al. J Clin Invest. 2004;114:1343 Genetic variation in ABCA1 contributes to HDL-C (~10%) Alrasadi M et al. Atherosclerosis 2006 ABCA1 mutations found in 20% of French Canadians with HDL deficiency.

ABCA1 gene variations in subjects with defective cellular lipid efflux
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 27 25 26 28 30 29 31 33 32 34 35 36 37 38 39 40 41 42 43 44 45 46 48 47 49 50 3’ 5’ UTR ABCA1 gene variations in subjects with defective cellular lipid efflux RDU 43/45% SBO 44/62% RPH 68/71% GOB 39/58% LBO 54/66% NL-12 89/59% R1851X 42G>T R219K P312P 30G>T 17C>T 794DA 14369T>C DCTC 2522C>A 26G>A 2520C>A G316G 24T>A V771M R1587K N1800H 18T>C Q2210H 8539C>T 9620G>A 9996-8 7792C>T 9087T>A 7420DT 8995G>A 238insG 270insG G616V 4152DA 889G>C 452DT I883M 23G>A 1258G>C splice site DGTT 296G>C L158L fs F1840L, L1869X 8549DT 8850T>G 8241T>A 9936DA 9996-8DGTT 9402G>A 9543G>A coding variant Heterozygous variant non coding variant Homozygous variant gene defect translation affected exon intron not sequenced ABCA1 mutations found in 20% of French Canadians with HDL <5%

Lipoprotein Metabolism
FFA Liver HL LPL Exogenous Pathway Chylo Remnant Chylomicron Peripheral Cells Free Cholesterol ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Intestine HL Steroidogenic Cells LCAT Nascent HDL HDL3 HDL2 LDL Liver ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Endogenous Pathway CETP PLTP Tg CE Liver 3 VLDL LPL HL IDL Feces FFA

{ { Modulators of HDL in Humans ApoA ApoA - - I I - - containing
LPL HL LCAT EL CETP { Extracellular factors s-PLA2 O O pre pre - - b b a a PLTP - 17.0 12.2 7.1 [nm] 9.5 [nm] [nm] - - 17.0 17.0 SMase - - 12.2 12.2 - - 9.5 9.5 ApoAI { - - 7.1 7.1 a a - - LpA LpA - - I I Cellular factors pre pre - - b b - - LpA LpA - - I I 1 1 SR-BI ApoA ApoA - - I I - - containing containing ABCA1 lipoproteins lipoproteins Lipases Gene defects identified in man Dastani Z et al. Figure 1

Candidate genes and HDL-C
Structural Receptor/Transport Lipases Exchange Apo AI ABCA1 Hep Lipase (LIPC) PLTP Apo AII NPC1 LPL CETP Endo Lipase LCAT S-PLA2 SMAse

The Proprotein convertase kexin/subtilisin type 5 gene (PSCK5) affects HDL-C
PCSK5 inactivates Endothelial Lipase (EL) directly and via ANGPTL3 expression Iatan I. Circ Cardiovasc Genet 2009 Oct

The PCSK5 gene (302 714 bp) contains 21 exons and is located on chr 9q21.13

PCSK5 gene SNPs SNP locations in the PCSK5 gene. Schematic representation of the human PCSK5 gene locus showing the exon structure and the location of the 19 variants (bottom panel) identified through sequencing and the 9 genetic variants associated with HDL-C (upper panel) identified by genotyping. SNPs in bold are associated with HDL-C with P<0.01. Locations are based on RefSeq NM_

Quantitative Trait Analysis PCSK5 and HDL-C Chromosome SNP Trait Beta
P-Value 9 rs HDL rs rs rs rs rs rs rs rs TRIG 0.5019 VLDL 0.1686 APOB 10.72

_ + HDL2 HDL3 EL EL Phospholipase activity PCSK5 Loss of function
Endothelial cells EL Phospholipase activity HSPG EL PCSK5 Loss of function ANGPLT3 + _ HDL3 Iatan I et al. Figure 2

The Genetics of HDL Genome-Wide Scans of Families
Genome-Wide Association Studies

Genome-Wide Scans and HDL-C

A Gene on Chromosome 16 affects HDL-C levels
WWOX: tumor suppressor gene contains 2 WW domains and a short-chain dehydrogenase domain (SRD). Expressed in Sterol producing tissues and in the liver

Figure 2 MouseQTL D16S514 D16S516 D16S505 D16S763 D16S3107 D16S3095
D8Mit12 LOD=3.5 MouseQTL CASPR4(CNTP) HSRG1(MON1B GABARAPL2 ADAMTS18 AK127004 BX648484 TERF2IP KIAA1576 CLECSF1 AF447709 KIAA0431 BC002701 PSMD7 RFWD3 WDR59 CTRB1 BCAR1 CHST6 CHST5 ADAT1 NUDT7 WWOX DNCL2B CDYL2 PKD1L2 BCMO1 GLG1 FA2H MLKL ZNRF1 LDHD CFDP1 ZFP1 KARS GCSH MAF DC13 GAN CIMP tel D16S514 8.1 D16S516 D16S505 D16S763 1.1 .6 10 D16S3107 D16S3095 D16S3106 D16S3066 D16S3018 D16S504 D16S3040 D16S507 D16S3098 2.6 1.4 0.8 3.2 18.1cM~7.8Mb LCAT CETP D16S503 D16S515 DiscreteLOD=1.7 QUE(D16S505) LOD(QTL)=2.3 QUE(95cM) RegionforSNPsassociationinSLSJ(23Mb) LOD(QTL)=2.55 SLSJ(85cM) D16S3140 1.8 7.4 25.5cM~18Mb C A B D cen 54.9 75.1 77.7 80.2 62.2 Figure 2

WWOX Protein WW domains indicates a role in protein-protein interactions. WWOX binds the proline-rich domain PPxY. Highest expression detected in hormonally regulated tissues such as testis, ovary, prostate. Expression pattern and presence of SRD domain suggests a role in steroid metabolism. Wwox-/- mice testis and ovaries display impaired gene expression of key steroidogenesis enzymes. Interrogation of several online databases show that WWOX is strongly associated with HDL-C (P = ). [Willer 08]

HDL Biological Networks
EL PCSK5 PLTP AGPL4 sPLA2 SMPD1 LPL ABCA1 Apo AI Apo E CETP HDL-C HL LCAT ? ? ? WWOX SR-B1 ABCG1

Genetics of HDL: Family Studies and Candidate Genes
Several genes account for ~25% of severe HDL deficiency (HDL-C <5th percentile) i.e.: A genetic basis for HDL is identified in 1-2% of subjects New genes (SMAse, PCSK5, WWOX) provide novel pathways in a complex network

HDL are More Complex than Imagined
J Clin Invest 2007:117:748

Vaisar, T. et al. J. Clin. Invest. 2007;117:746-756
Copyright ©2007 American Society for Clinical Investigation

Questions? Second session 21 Jan 2010

Genome-Wide Association Studies (GWAS)
Katherisan S, Willer C, Nat Genet 2009

73

The yet identified genes together explain only a small amount of less than 10% of the HDLC variance, which leaves an enormous room for further yet to be identified genetic variants. This might be accomplished by large population-based genome-wide meta-analyses and by deep-sequencing approaches on the identified genes. The resulting findings will probably result in a re-drawing and extension of the involved metabolic pathways of HDLC metabolism. Exp Gerontol 2008

Genome-Wide Scans and Quantitative traits
Broad and Lund database Wellcome-Trust Case Control Consortium (WTCCC) Framingham Study Database Fusion/Sardinia/FHS

Common variants at 30 loci contribute to polygenic dyslipidemia
Sekar Kathiresan, Cristen J Willer et al. Nat Genet 2009;41;36

Common variants at 30 loci contribute to polygenic dyslipidemia
Sekar Kathiresan, Cristen J Willer et al. Nat Genet 2009;41;36 Genes you have seen before in candidate gene approach

Common variants contribute to Lipoprotein Lipid Levels
Cristen J Willer et al. Available on line (

GWAS HDL-C Trait Trait Chrom SNP P val Gene MAF Effect (SD) HDL 11q12
Sekar Kathiresan, Cristen J Willer et al. Nat Genet 2009;41;36 Trait Chrom SNP P val Gene MAF Effect (SD) HDL 11q12 rs174547 2x10-12 FADS1-2-3 T, C (0.33) –0.09(0.02) 16q22 rs 9x10-13 LCAT G, A (0.11) +0.07 (0.03 9p22 rs471364 3x10-10 TTC39B T, C (0.12) –0.08 (0.03) 20q13 rs 8x10-10 HNF4A C, T (0.03) –0.19 (0.05) rs7679 4x10-9 PLTP T, C (0.19) –0.07 (0.02) 19p13 rs 1x10-8 ANGPTL4 C, T (0.16) –0.12 (0.04) 16q13 rs173539 4x10-75 CETP C, T (0.32)c +0.25 (0.02) 8p21 rs 2x10-34 LPL A, G (0.10)c +0.23 (0.03) 15q22 rs 8x10-23 LIPC (HL) C, T (0.30)c +0.10 (0.02) 18q21 rs 7x10-15 LIPG C, T (0.17) –0.14 (0.02) 1q23 rs964184 1x10-12 A1-C3-A4-A5 C, G (0.14)c –0.17 (0.03) 12q24 rs 1x10-10 MMAB, MVK G, C (0.45) 9q31 rs 1x10-9 ABCA1 C, T (0.26)c –0.08 (0.02) 1q42 rs 4x10-8 GALNT2 A, G (0.40) –0.05 (0.02)

Common variants at 14 loci contribute to HDL-C
Sekar Kathiresan, Cristen J Willer et al. Nat Genet 2009;41;36 Based on combined GWAS analysis of >40,000 subjects, 11% of variance of HDL-C levels can be explained.

The Genetics of HDL: Impact on HDL-C or CAD?
Monogenic Disorders Genome-wide Associations Association with CAD

Mendelian randomization is a method of using non-experimental studies to examine the causal effect of a modifiable exposure on disease by making use of measured variation in genes of known function.

Mendelian Randomization
Implies causality of a gene product (intermediary phenotype) in a disease process Gene IP Often used, perhaps wrongfully, to dismiss a gene or its product as a causal factor

Copenhagen Heart Study: HDL-C and CVD Risk
Frikke-Schmidt R JAMA. 2008;299(21):

Copenhagen Heart Study: ABCA1 Mutations and CVD Risk
Frikke-Schmidt R JAMA. 2008;299(21):

HDL-C Epidemiology Observations:
Risk of CHD varies continuously and inversely with HDL-C levels. CHD risk decreases by 50% for each 0.52 mmol/L increase in HDL-C (unproven). 4.0 4.0 3.0 CHD risk ratio 2.0 2.0 Epidemiology The author demonstrates from Framingham data that the risk of coronary heart disease (CHD) varies continuously and inversely with HDL-C levels. The CHD risk decreases by 50% for each 0.52 mmol/L increase in HDL-C. Other authors have suggested that cumulative epidemiological evidence now suggests a 2 to 3 percent reduction in the risk of developing CHD for for every 0.03 mmol/L increase in HDL-C levels. Kannel WB. High-Density Lipoproteins: Epidmiologic Profile and Risks of Coronary Artery Disease. AJC, August 22, 1983; Volume 52 1.0 1.0 0.65 1.17 1.68 HDL-C (mmol/L) Kannel WB. AJC 1983;52,9B-12B

HDL Epidemiology: Yin and Yang
4.0 4.0 3.0 CHD risk ratio ABCA1** CV Risk CETP Deficiency (▲ CV Risk) 2.0 2.0 Epidemiology The author demonstrates from Framingham data that the risk of coronary heart disease (CHD) varies continuously and inversely with HDL-C levels. The CHD risk decreases by 50% for each 0.52 mmol/L increase in HDL-C. Other authors have suggested that cumulative epidemiological evidence now suggests a 2 to 3 percent reduction in the risk of developing CHD for for every 0.03 mmol/L increase in HDL-C levels. Kannel WB. High-Density Lipoproteins: Epidmiologic Profile and Risks of Coronary Artery Disease. AJC, August 22, 1983; Volume 52 ABCA1* 1.0 1.0 LCAT HL (LIPC) Apo AI Milano (▼ CV Risk) 0.65 1.17 1.68 3.16 *Copenhagen Heart Study ** Wellington S, Genest J HDL-C (mmol/L)

Genome-Wide Associations (GWA) Studies

The Genetics of Complex traits
Genome-Wide Scans of Families Genome-Wide Association Studies

90

Genome-Wide Scans for CAD and MI

(Lack of ) Validation of Genetic Markers for CAD
Morgan T et al. JAMA 2007;297:1551

The Genetics of Continuous traits
Heritability Segregation Studies Genome-Wide Scans of Families Quantitative Trait Loci (QTL) Genome-Wide Association Studies Mouse Synthenic Regions

Phenotype Distance Genetics of complex traits: longer phenotype distance decreases specificity Lipid Levels Biol. Pathways IMT CHD death, MI Surrogate End-Points Mortality/ Morbidity Risk Factor Biomarkers Phenotype Distance

Genome-Wide Scans and CAD: Chromosome 9q21 locus
McPherson R. Science 2007;316:1488 Helgdottir A. Science 2007;316:1491 WTCCC Nature 2007;447:661 Samani NJ. NEJM 2007;357:443 Drinking from the fire hose –Statistical issues in genome-wide association studies: Hunter DJ. NEJM 2007;357:436

Genome-Wide Scans for CAD and MI
Samani NJ. NEJM 2007;357:443

Chromosome 9q21: which gene?

Meta-analysis of 9p21 and heart disease
Schunkert et al. Circulation 2008

Women’s Genome Health Study GWAS for Plasma C-Reactive Protein Level
Am J Hum Genet 2008;82:

Danish population Study of SNPs, OR CRP 1.6, SNPs increased CRP up to 64%. No relationship with SNPs and outcome. This data demonstrates that genetics determined outcomes in a gene that controlled LDL levels, whereas this was not the case with CRP SNPs. Suggests CRP is not causative but a marker of risk. CRP Genetics and Outcome Zacko et al NEJM 2008;359:1897. 101

Epigenetics

DNA Methylation Transcriptional regulation Genome stabilization
DNMTs Transcriptional regulation Genome stabilization Genomic imprinting X-inactivation Cancer ICF, RETT syndrome Prader-Willi, Angelman, Beckwith-Wiedemann syndromes

Imprinted Genes DNA from 400 oocytes  Bisulfite genomic sequencing
Igf2r DMR2 7 CpGs Snrpn DMR1 16 CpGs Peg1/Mest Promoter & exon 1 23 CpGs Peg3 Promoter & exon 1 18 CpGs DNA from 400 oocytes  Bisulfite genomic sequencing

The Epigenome Nature 429:457, 2004

Human Diseases Associated with Altered Methylation Profiles
Cancer Inactivation of tumor suppressor genes Inactivation of DNA repair genes CpG island hypermethylation Normal DNA methylation Global hypomethylation Chromosome instability Retrotransposon activation Oncogene activation ? Adapted from Strathdee et al., Expert Reviews in Molecular Medicine (2002). Imprinting Diseases - Angelman Syndrome - Prader-Willi Syndrome - Beckwith-Wiedemann Syndrome ICF Syndrome Mutation in DNMT3B  hypomethylation of centromeric chromatin Immunodeficiency, Centromeric region instability, Facial anomalies

Imprinted Genes Loss of Maternal Methylation at SNRPN and KCNQ1OT1
PAR5 SNURF-SNRPN PAR-SN ZNF217 NDN MAGEL2 IPW PAR1 UBE3A GABRB3 GABRA5 GABRG3 UBE3A-AS IC ZNF217-AS Angelman and Prader-Willi syndromes locus 15q11-q13 H19 INS IGF2 ASCL2 KCNQ1OT1 KCNQ1 CDKN1C CD81 TH IGF2-AS TSSC5 TSSC3 NAP1L4 WT1 Beckwith-Wiedemann syndrome locus 11p15.5 Loss of Maternal Methylation at SNRPN and KCNQ1OT1

Female Predominance and Transmission Distortion in the Long-QT Syndrome
Long QT syndrome caused by KCNQ1 and KCNH2 mutations Autosomal Dominant Transmission Ratio 55% Female; 45% Male (p=0.005 from normal) Possible genomic imprinting Imboden M et al, NEJM 2007;355:

EPIGENETICS and CVD Long-QT syndrome, types 1 and 2, are caused by mutations in the potassium-channel genes KCNQ1 and KCNH2 Female Predominance and Transmission Distortion in the Long-QT Syndrome Imbodem M. NEJM 2006; 355:

http://www. mgu. har. mrc. ac. uk/research/imprinting/imprin-viewmaps

Human Biochemical Genetics 2009 Genetics of Cardiovascular Diseases
General Principles Historical Aspects Monogenic Disorders Genome-wide Association Studies (GWA) Mendelian Randomization Epigenetics

Genetics of Cardiovascular Diseases

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